Nitric oxide (NO) is an important signaling molecule, and a number of NO synthesis inhibitors and scavengers have been developed to allow study of NO functions, and to reduce excess NO levels in disease states.
Septic shock is characterized by refractory hypotension, and has an extremely high mortality rate. Various cytokines and signaling molecules contribute to the septic state, with nitric oxide (NO) playing a major role in the development of the hypotension. NO is produced by three different NO synthases: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). A marked induction of iNOS is largely responsible for the increased NO levels in sepsis. Non-selective NOS inhibitors showed some success in animal models of sepsis, but in a large Phase III trial one of these agents resulted in side effects and increased mortality. Selective iNOS inhibitors have shown more promise in animal models, but have yet to be tried in humans. Another approach to lower NO levels in sepsis is to use an NO scavenger, and several NO scavengers including hemoglobin, dithiocarbamate derivatives, and vitamin B12 (cobalamin) have been shown to be beneficial in animal models of sepsis. Cobalamin had been previously demonstrated to bind NO, and thereby inhibit the vitamin B12-dependent enzyme methionine synthetase (Danishpajooh, J. Biol. Chem. 276:27296-27303, 2001).
Cyanide is a highly toxic agent which inhibits mitochondrial cytochrome c oxidase, thereby depleting cellular ATP. It contributes to smoke inhalation deaths in fires, and could be used as a weapon of mass destruction. Cyanide is generated in household fires due to the high amount of plastic material that is usually present. Cobalamin has been used to treat cyanide toxicity in Europe, and although it has been shown to be highly effective, it has not been used in this country. Similarly, carbon monoxide (CO) is generated in fires and the most common cause of death in fires is smoke inhalation, and in particular inhalation of cyanide and CO.
Therefore, it would be desirable to provide new methods and compositions for preventing and treating excess nitric oxide or excess cyanide in subjects with no adverse side effects. The methods and pharmaceutical compositions of the present invention are directed toward these, as well as other, important ends.